Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

• the present invention relates generally to the art of chemistry and more particularly to the production of (a) novel organosilane derivatives of 6-aminopenicillanic acid, and (b) acylated derivatives of said organosilane derivatives of 6-aminopenicillanic acid, which readily provide, on hydrolysis or alcoholysis, the corresponding penicillins known to have useful antibiotic activity.
• the present invention is based on the discovery that, not only are said diand tri-halosilanes in fact useable for preparing solvent soluble organosilane derivatives of fi-aminopenicillanic acid, and therefrom, the acylated organosilane products ultimately useful for hydrolysis or alcoholysis to penicillins, but, moreover, result in excellent yields and purity of the final penicillin products.
• the silylated derivatives of 6-aminopenicillanic acid which are by definition tri-organo substituted, e.g., trirnethylsilyl-, derivatives
• the products of 3,654,266 Patented Apr. 4, 1972 "Ice the present invention are di-organo substituted silane derivatives, and these are herein designated silenated derivatives.
• R is of the group consisting of hydrogen, alkyl, aryl and aralkyl
• R is of the group consisting of halogen, alkyl, aryl and aralkyl
• R is of the group consisting of hydrogen, and the alkanoyl, aroyl and aralkanoyl residues of organic carboxylic acids;
• R and R have the same meaning as before, and X is halogen
• n is an integer from 0 to -1;
• n is an integer from 1 to about 25;
• p is an integer from 0 to 1;
• Y is of the group consisting of halogen, and groups of the following formula:
• R is hydrogen
• the new silenated 6-arninopenicillanic acid derivatives of Formula I, wherein R is hydrogen are prepared by reaction of 6-aminopenicillanic acid, or a salt thereof, preferably with heating in the presence of an acid acceptor, and also preferably in an inert organic solvent, with a dior tri-halosilane of the following formula:
• R R and X have the same meanings as in Formula I above, and the reaction is continued until formation of the salt of the respective hydrogen halide is substantially complete or until substantially all 6-aminopenicillanic acid is reacted.
• Suitable dior tri-halosilanes including for example, dimethyldichlorosilane, methylpropyldichlorosilane, dimethyldibromosilane, dibutyldichlorosilane, diphenyldichlorosilane, methylphenyldichlorosilreacted.
• the reaction between APA and a dior tri-halosilane is carried out preferably at a temperature at which the reaction proceeds to completion in a reasonably short time, for example, between 10 C. and the boiling point of the solvent media.
• a temperature at which the reaction proceeds to completion in a reasonably short time for example, between 10 C. and the boiling point of the solvent media.
• the reaction of one mole of APA with one mole of dimethyldichlorosilane in the presence of two moles of triethylamine is complete in three hours, Whereas after only one hour, about 4% of the APA remains unreacted.
• Complete solubility of the APA used as a starting material and a quantitative yield of triethylamine hydrochloride are indicative of complete reaction.
• the silenated '6-aminopenicillanic acid derivatives prepared according to this invention can be isolated by 1 2 o R l.
• n 1 in the foregoing formulae are considered to be linear or cyclic dimers, trimers and the like, or polymers.
• the repeating A PA moieties of the group units may be randomly disposed head-toward-tail, head-toward-head and/ or tail-toward-tail in a given compound, as will be understood by those skilled in the art and referred to hereinbefore.
• Suitable acid acceptors include ammonia, organic amines, alkali metal carbonates, alkaline earth metal carbonates and the like. In general, it is preferred to use about two moles of anhydrous ammonia or an amine, such as triethylamine or diethylamine, per mole of halosilane.
• anhydrous non-hydroxylic organic solvents are suitable, including hydrocarbons, such as benzene and toluene; chlorinated solvents such as methylene chloride, chloroform, ethylene dichloride and chlorobenzene; ethers such as diethyl ether, dioxane and tetrahydrofuran; and other conventional solvents such as methylisobutylketone, dimethylformamide, ethyl acetate and acetonitrile.
• hydrocarbons such as benzene and toluene
• chlorinated solvents such as methylene chloride, chloroform, ethylene dichloride and chlorobenzene
• ethers such as diethyl ether, dioxane and tetrahydrofuran
• other conventional solvents such as methylisobutylketone, dimethylformamide, ethyl acetate and acetonitrile.
• solvents employed as reaction media must be substantially anhydrous and free from alcoholic impurities. Although more than ml. of solvent per g. of APA has been used successfully for the silenation reaction, the use of 10 ml. per g. is usually sufficient.
• reaction mixture can be acylated directly without filtration or concentration.
• the new silenated derivatives of APA are readily soluble in a wide selection of anhydrous, non-hydroxylic solvents such as methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, dioxane, benzene, toluene, dimethylsulfoxide, dimethylacetamide, dimethylformamide, acetonitrile, acetone, and methylisobutylketone, but are largely insoluble in hexane and cyclohexane.
• anhydrous, non-hydroxylic solvents such as methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, dioxane, benzene, toluene, dimethylsulfoxide, dimethylacetamide, dimethylformamide, acetonitrile, acetone, and methylisobutylket
• the fi-lactam ring of the silenated derivatives is shown to be intact by infrared analysis as well as by the recovery of high purity APA on treatment with water or an alcohol.
• NMR studies and elemental analysis indicate a 1:1 ratio of Si to APA nucleus and absence of halogen, which is consistent with the structures shown for the products of these reactions.
• the new acylated organosilane derivatives of APA of Formula I wherein R is an acyl group are prepared by reaction of the silenated APA intermediates with a suitable reactive derivative of an organic carboxylic acid in the presence of an acid acceptor.
• the reactive derivative may be that of a suitable organic sulfonic acid instead of an organic carboxylic acid.
• the ultimate penicillins are obtained by hydrolysis or alcoholysis of these acylated derivatives to the penicillin per se.
• Suitable acylating agents include carboxylic acid halides, carboxylic acid anhydrides, mixed anhydrides with other carboxylic or inorganic acids, esters such as thiol esters and phenolic esters, lactones, and carboxylic acids with carbodiimides or N,N'-carbonyldiimid azoles.
• esters such as thiol esters and phenolic esters, lactones
• carboxylic acids with carbodiimides or N,N'-carbonyldiimid azoles for the preparation of aminopenicillins, amino acid chloride hydrochlorides and amino acid N-carboxyanhydrides are suitable for acylating the APA derivatives.
• silenated penicillin derivatives of particular interest are those of Formula I wherein R is of the group consisting of those groups having one of the following formulae:
• R and R are of the group consisting of hydrogen and lower alkoxy; and j is an integer from to 1;
• R has the same meaning as in Formula V above:
• R is of the group consisting of hydrogen, lower alkvl and phenyl
• R has the same meaning as in Formula VII above, and R and R" are of the group consisting of hydrogen and halogen;
• R and R are of the group consisting of hydrogen, lower alkyl, alkoxy, phenyl and phenoxy; r is an integer from 0 to l, and s is an integer from 1 to 3, with the provisos that when r is 0, s is greater than 1, and when r is l, s is less than 3; and
• acylating agents which may be used are the following: phenoxyacetyl chloride, 2,6-dimethoxybenzoyl chloride, benzenesulfonyl chloride, 2-phenoxypropionyl chloride, 2-phenoxybutyryl chloride, D()phenylglycyl chloride HCl, 1-
• aminocyclopentanecarboxylic acid chloride HCl aminocyclopentanecarboxylic acid chloride HCl, l-aminocyclohexanecarboxylic acid chloride HCl, 2-amino-2- carboxyindane acid chloride HCl, 2-ethoxynaphthoyl bromide and 3-(2,6-dichlorophenyl)-5-methylisoazole-4-carbonyl chloride.
• the acylation reaction is carried out preferably in the presence of an acid acceptor which may be the same or different from the one employed in preparing the silenated intermediate.
• an acid acceptor which may be the same or different from the one employed in preparing the silenated intermediate.
• a tertiary amine such as triethylamine
• a weaker base such as N,N-dimethylaniline, pyridine, or quinoline
• an excess strong amine if present, by addition of a mineral acid salt of a weak amine.
• a mineral acid salt of a weak amine for example, using one mole of dimethyldichlorosilane and an excess (e.g., 2.3 moles) of triethylamine in the silylation of one mole of 6-aminopenicillanic acid, the addition of 0.4 equivalent of dimethylaniline 2HC1 prior to acylation with phenylglycyl chloride HCl increased the overall yield of anhydrous ampicillin from 70 to 83% of theory.
• silenated penicillins of the present invention are readily hydrolyzed or alcoholyzed by treating with water or other hydroxy-containing compound, e.g., an alcohol such as methyl or ethyl alcohol, to form the corresponding penicillins.
• water or other hydroxy-containing compound e.g., an alcohol such as methyl or ethyl alcohol
• EXAMPLE 1 In a 1 liter, 3-neck flask fitted with stirrer, thermometer, and drying tube, 40.5 g. (0.40 mole) of triethylamine was added to a mixture of 43.2 g. (0.20 mole) of 6-aminopenicillanic acid (APA) and 425 ml. of dry acetonitrile under a nitrogen atmosphere. At 10-15 C., 25.8 g. (0.20 mole) of dimethyldichlorosilane was added dropwise, and then the mixture was stirred at 45 C. for one hour. After cooling to 15 C., the insoluble material was removed by filtration, washed with acetonitrile, and dried; weight 48.3 g. or 88% of theory for triethylamine hydrochloride. Complete water-solubility showed absence of unreacted APA.
• APA 6-aminopenicillanic acid
• This silenated APA was completely soluble at 20 C. in anhydrous solvents such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, ethylacetate, tetrahydrofuran, dioxane, benzene, toluene, dimethylsulfoxide, dimethylacetamide, dimethylformamide and acetonitrile, but largely insoluble in hexane and cyclohexane.
• anhydrous solvents such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, ethylacetate, tetrahydrofuran, dioxane, benzene, toluene, dimethylsulfoxide, dimethylacetamide, dimethylformamide and acetonitrile, but largely insoluble in hexane and cyclohexane.
• EXAMPLE 4 By a procedure similar to Example 1, a mixture of 21.6 g. (0.10 mole) of APA, 213 ml. of methylene chloride, and 20.3 g. (0.20 mole) of triethylamine was treated with 15.7 g. (0.10 mole) of methylpropyldichlorosilane with cooling. After refluxing gently for two hours and cooling to C., the insoluble material was removed by filtration and washed with methylene chloride. Solubilization of the triethylamine hydrochloride by stirring in water left 0.4 g. of unreacted APA.
• the product was soluble at 20 C. in anhydrous solvents including CH Cl tetrahydrofuran, acetone, benzene and dimethylformamide.
• EXAMPLE 7 Dicloxacillin (acid) A methylene chloride solution of silenated APA was prepared from 0.20 mole of APA and dimethyldichlorosilane as described in Example 3. After removing triethylamine hydrochloride by filtration, the filtrate was treated with 26.7 g. (0.22 mole) of N,N-dimethylaniline, and then a solution of 58.2 g. (0.20 mole) of 3-(2,6- dichlorophenyl)-5-methylisoxazole-4-carbonyl chloride in 75 ml. of methylene chloride was added at 0 C. over 15 minutes. The mixture was allowed to warm to room temperature and stirred for an additional hour.
• EXAMPLE 8 Nafci'llin (acid) A methylene chloride solution of silenated APA was prepared from 0.20 mole of APA as described in Example 3. After removing triethylamine hydrochloride by rfiltration, the filtrate was treated with 26.7 g. of N,N-dimethylaniline, and then 47.5 g. (0.202 mole) of 2-ethoxynaphthoyl chloride was added portionwise over 20 minutes at 0 C.
• the wet filter cake was heated in a mixture of 220 ml. of isopropanol and 19.4 g. of triethylamine at 7078 C. for 15 minutes, filtered, and the product washed with 85% isopropanol.
• the yield of dried ampicillin anhydrous amounted to 5 8.0 g. or 83% of theory from APA; iodometric assay, 1010 mcg. per mg; bioassay, 1015 mcg. per mg.
• ampicillin was prepared when the quantity of dimethyldichlorosilane was decreased to 14.2 g. (0.11 mole) and increased to 51.7 g. (0.40 mole) and when the triethylamine was replaced by 2,2'-diethyldihexylamine.
• IEXAMPL'E 11 6- 1-aminocyclohexanecarboxamido Penicillanic acid A methylene chloride solution of silenated APA was prepared from 0.20 mole of APA as described in Example 3. Without removing triethylamine hydrochloride by filtration, the mixture was treated with 16.6 g. of pyridine, and then 40.7 g. (0.205 mole) of l-amino-l-cyclohexanecarboxylic acid chloride hydrochloride was added portionwise over minutes at 0 C. After stirring at 0 C. and finally at 20 C. for one hour, the reaction mixture was poured into 400 ml. of water, clarified by filtration, and adjusted to pH 5.4 by adding dilute sodium hydroxide solution.
• Penicillin V A methylene chloride solution of silenated APA- was prepared from 0.10 mole of APA and methylpropyldichlorosilane as described in Example 4. After removing triethylamine hydrochloride, the pale yellow filtrate was treated with 13.4 g. of N,N-dimethylaniline, and then a solution of 17.0 g. (0.10 mole) of phenoxyacetal chloride in '50 ml. of methylene chloride was added at 0 C. over 20 minutes. The mixture was allowed to stir at 20 C. for 1 /2 hours.
• EXAMPLE 13 6- 2-almino-2-indancarboxamido penicillanic acid
• Amethylene chloride solution of silenated APA was prepared from 0.10 mole of APA as described in Example 3. After removing triethylamine hydrochloride fby filtration, 13.4 g. of N, N-dimethylaniline was added to the filtrate followed by the addition of 24.2 g. (0.104 mole) of 2-amino-2-carboxyindane acid chloride hydrochloride in small portions over 20 minutes at 0 C. The mixture was allowed to warmto room temperature and stir for an additional 15 minutes.
• EXAMPLE 15 Ampicillin Substituting 23.0 g. (0.20 mole) of methyldichlorosilane (CH SiHCl for dimethyldichlorosilane in the procedure of Example 9, 48.0 g. of ampicillin anhydrous, corresponding to 69% of theory, was obtained, iodometric assay, 1004 mcg. per mg.
• EXAMPLE 16 Following the procedure of Example 7, a series of silenated penicillin derivatives are prepared, and from them the corresponding penicillins per se by substituting, for the 3-(2,6-dichlorophenyl)-5-methylisooxazole-4carbonyl chloride as acylating agent, equivalent amounts of the acylating agents set forth in Table A below:
• X. I clalm wherein R and R are of the group consisting of hy- I 1.
• R and R are of the group consisting of hy- I 1.
• e e R R is of the group consisting of hydrogen, lower alkyl, phenyl, lower alkylphenyl and benzyl; 51
• R is of the group consisting of halo, lower alkyl, phenyl, li
• Ra is of the group consisting of hydrogen, d those wherein R and R have the same meaning as before,
• n 1s an integer from 0 to 1; n is an integer from 1 to about 25;
• R and R are of the group consisting of hy- 3*? drogen and lower alkoxy; and j is an integer from 0 to l o fi c ⁇ i c I! R 0 o H II. 0 wherein R has the same meaning as before; with the provisos that, in Formula I.,
• R has the same meaning as in Formula V above; 60
• R is of the group consisting of hydrogen and phenyl
• R and R are of the group consisting of hydrogen and lower alkoxy; and j is an integer from to 1;
• R has the same meaning as in Formula V above;
• R is of the group consisting of hydrogen, lower alkyl and phenyl
• q is an integer from 1 to 5;
• R has the same meaning as in Formula VII above, and R and R are of the group consisting of hydrogen and halogen;
• R and R are of the group consisting of hydrogen, lower alkyl, lower alkoxy, phenyl and phenoxy; r is an integer from 0 to l, and s is an integer 14 from 1 to 3, with the provisos that when r is 0, s is greater than 1, and when r is 1, s is less than 3; and
• a process for preparing organosilane derivatives of 6-arninopenicillanic acid comprises: reacting 6-aminopencillanic acid with a dior trihalosil'ane of the following formula:
• R is of the group consisting of lower alkyl, phenyl and lower alkylphenyl
• R is of the group consisting of hydrogen, halogen, lower alkyl, phenyl and lower alkylphenyl;
• X is halogen; 15 in an anhydrous non-hydroxylic organic solvent in the presence of an acid acceptor; and wherein:
• the mole proportions of each of said 6-aminopenicillanic acid, said dior tri-halosilane, and said acid acceptor are from 1 to 2.
• a process for preparing a penicillin which comprises subjecting the organosilane derivative of 6-aminopenicillanic acid obtained by the process of claim 17, to a treatment selected from the group consisting of hydrolysis and alcoholysis to obtain the corresponding penicillin.
• acylating agent comprises a group selected from the following groups:
• R ew R 0 wherein R and R are of the group consisting of hydrogen and lower alkoxy; and j is an integer from 0 to 1;
• R is of the group consisting of hydrogen and phenyl
• R and R are of the group consisting of hydrogen, lower alkyl, lower alkoxy, phenyl and phenoxy, r is an integer from 0 to l, and s is an integer from 1 to 3, with the provisos that when r is 0, s is greater than 1, and when r is 1, s is less than 3; and
• a process for preparing organosilane derivatives of G-aminopenicillanic acid comprises: reacting 6-arninopenicillanic acid with a dihalosilane of the following formula:
• R is of the group consisting of hydrogen, lower alkyl,
• R is of the group consisting of lower alkyl, phenyl and lower alkylphenyl
• X is halogen in an anhydrous non-hydroxylic organic solvent in the presence of an acid acceptor; and acylating the or-ganosilane derivative obtained, again in an anhydrous non-hydroxylic organic solvent, with a reactive derivative of an organic carboxylic acid selected from those containing one of the following groups:
• the mole proportions of each of said 6-aminopenicillanic acid, said dior tri-halosilane, and said acid acceptor are from 1 to 2.
• W is of thegroup consisting of hydrogen

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• 1968
  • 1968-05-08 US US727688A patent/US3654266A/en not_active Expired - Lifetime
• 1969
  • 1969-04-24 CA CA049,617A patent/CA992957A/en not_active Expired
  • 1969-04-25 IL IL32078A patent/IL32078A/xx unknown
  • 1969-04-25 IL IL41851A patent/IL41851A/xx unknown
  • 1969-05-06 PH PH10287A patent/PH10525A/en unknown
  • 1969-05-06 GB GB1266544D patent/GB1266544A/en not_active Expired
  • 1969-05-07 DK DK249669AA patent/DK137760B/da not_active IP Right Cessation
  • 1969-05-07 NL NLAANVRAGE6906997,A patent/NL173406C/xx not_active IP Right Cessation
  • 1969-05-08 FR FR6914872A patent/FR2008111A1/fr active Pending
  • 1969-05-08 SE SE7211003A patent/SE395702B/sv unknown
  • 1969-05-08 FI FI1358/69A patent/FI56181C/fi active
  • 1969-05-08 SE SE6906553A patent/SE410461B/sv unknown
  • 1969-05-08 CH CH707669A patent/CH515933A/de not_active IP Right Cessation
  • 1969-05-08 DE DE1923624A patent/DE1923624C3/de not_active Expired
  • 1969-05-08 BR BR208638/69A patent/BR6908638D0/pt unknown
  • 1969-05-08 BE BE732769D patent/BE732769A/xx not_active IP Right Cessation
  • 1969-05-08 JP JP44035465A patent/JPS518954B1/ja active Pending
• 1971
  • 1971-07-02 JP JP46048726A patent/JPS5114517B1/ja active Pending
  • 1971-07-02 JP JP46048725A patent/JPS5111639B1/ja active Pending
• 1972
  • 1972-01-06 DK DK6872A patent/DK143563C/da not_active IP Right Cessation
  • 1972-01-06 DK DK7072A patent/DK147127C/da not_active IP Right Cessation
  • 1972-04-17 SE SE7205606A patent/SE419088B/sv unknown
  • 1972-04-27 SE SE7205607-0A patent/SE419089B/sv unknown
• 1973
  • 1973-10-09 PH PH15103A patent/PH11955A/en unknown
  • 1973-10-09 PH PH15102A patent/PH11783A/en unknown
• 1975
  • 1975-12-30 MY MY61/75A patent/MY7500061A/xx unknown

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